Article ; Online: Madecassoside ameliorates bleomycin-induced pulmonary fibrosis in mice through promoting the generation of hepatocyte growth factor via PPAR-γ in colon.
British journal of pharmacology
2016 Volume 173, Issue 7, Page(s) 1219–1235
Abstract: ... of hepatocyte growth factor (HGF) in colon tissues, and HGF receptor antagonists attenuated its anti-PF effect. Madecassoside ... anti-PF effects induced by p.o. madecassoside in mice are not mediated by its metabolites or ... effect in mice. However, i.p. madecassoside had no anti-PF effect. Madecassoside increased the expression ...
| Abstract | Background and purpose: Madecassoside has potent anti-pulmonary fibrosis (PF) effects when administered p.o., despite having extremely low oral bioavailability. Herein, we explored the mechanism of this anti-PF effect with regard to gut hormones. Experimental approach: A PF model was established in mice by intratracheal instillation of bleomycin. Haematoxylin and eosin stain and Masson's trichrome stain were used to assess histological changes in the lung. Quantitative-PCR and Western blot detected mRNA and protein levels, respectively, and cytokines were measured by ELISA. Small interfering RNA was used for gene-silencing. EMSA was applied to detect DNA-binding activity. Key results: Administration of madecassoside, p.o., but not its main metabolite madecassic acid, exhibited a direct anti-PF effect in mice. However, i.p. madecassoside had no anti-PF effect. Madecassoside increased the expression of hepatocyte growth factor (HGF) in colon tissues, and HGF receptor antagonists attenuated its anti-PF effect. Madecassoside facilitated the secretion of HGF from colonic epithelial cells by activating the PPAR-γ pathway, as shown by an up-regulation of PPAR-γ mRNA expression, nuclear translocation and DNA-binding activity both in vitro and in vivo. Also GW9662, a selective PPAR-γ antagonist, almost completely prevented the madecassoside-induced increased expression of HGF and amelioration of PF. Conclusions and implications: The potent anti-PF effects induced by p.o. madecassoside in mice are not mediated by its metabolites or itself after absorption into blood. Instead, madecassoside increases the activity of PPAR-γ, which subsequently increases HGF expression in colonic epithelial cells. HGF then enters into the circulation and lung tissue to exert an anti-PF effect. |
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| MeSH term(s) | Animals ; Bleomycin ; Cell Line, Tumor ; Cell Survival/drug effects ; Colon/drug effects ; Colon/metabolism ; Female ; Gene Silencing ; Hepatocyte Growth Factor/antagonists & inhibitors ; Hepatocyte Growth Factor/metabolism ; Intestinal Mucosa/drug effects ; Intestinal Mucosa/metabolism ; Lung/drug effects ; Lung/pathology ; Mice, Inbred ICR ; PPAR gamma/antagonists & inhibitors ; PPAR gamma/genetics ; PPAR gamma/metabolism ; Pulmonary Fibrosis/chemically induced ; Pulmonary Fibrosis/drug therapy ; Pulmonary Fibrosis/metabolism ; Triterpenes/pharmacology ; Triterpenes/therapeutic use | |||||
| Chemical Substances | PPAR gamma ; Triterpenes ; Bleomycin (11056-06-7) ; Hepatocyte Growth Factor (67256-21-7) ; madecassoside (CQ2F5O6YIY) ; madecassic acid (M7O1N24J82) | |||||
| Language | English | |||||
| Publishing date | 2016-02-25 | |||||
| Publishing country | England | |||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 80081-8 | |||||
| ISSN | 1476-5381 ; 0007-1188 | |||||
| ISSN (online) | 1476-5381 | |||||
| ISSN | 0007-1188 | |||||
| DOI | 10.1111/bph.13421 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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